The objective of this project is to examine the pathogenesis of SIVagm in African green monkeys (AGMs). This species is able to cope with high levels of SIVagm replication without negative consequences. Our understanding of how AGMs are able to do this is limited. Our preliminary results depict a paradox of SIVagm infection in AGMs, characterized by: a) high plasma VLs, equivalent to pathogenic SIV infections; b) a paucity of "classical" SIV target cells (defined as CD4+CCR5+CD45RAneg T cells and; c) preservation of CD4+ T cells in chronic SIVagm infection. Therefore, we hypothesize that there are quantitative differences in target cells, immune cell phenotypes, sites of tissue viral replication and in vivo viral dynamics between pathogenic and non-pathogenic SIV infections which may explain the resistance to AIDS in this natural host. To examine this hypothesis, we propose the following Specific Aims (SA): SA1: To compare the pathogenesis of SIVagm in AGMs of Carribean origin to that of a heterologous host susceptible to AIDS caused by SIVagm; pig-tailed macaques (PTMs). A different clinical outcome of SIVagm infection was reported for these two species, but studies were limited to VLs in plasma. Few immunologic data is available for SIVagm-infected AGMs and PTMs. Therefore, our proposal will focus on viral and immunological parameters in tissues of SIVagm-infected AGMs and PTMs. We will compare these two hosts infected with the same SIVagm strain for sites of viral replication, cell phenotypes, proliferation and apoptosis. Also, the major target cells for SIVagm will be determined in both hosts. SA2: To examine SIVagm viral dynamics in vivo, and to determine the relative contribution of short and long-lived cells to the total plasma viral loads in SIVagm-infected AGMs and PTMs. The paradox of SIVagm infection in its natural host suggests potential differences between pathogenic and non-pathogenic models in viral burst size, viral clearance rates or the life span of various types of target cells. We will compare the in vivo dynamics and target cells of SIVagm in AGMs and PTMs, using similar approaches that have been used for SIVmac and HIV-1. Combined, these aims are designed to determine the viral and/or host factors responsible for resistance to AIDS.